4-Pyridinylmethyl-Morpholine Derivatives and the use thereof as Medicament

ABSTRACT

and pharmaceutically acceptable salts thereof, wherein R1 and R2 are defined herein. Also disclosed are processes for their preparation, pharmaceutical compositions containing the compounds, and their use in therapy, particularly in the treatment or prevention of conditions having an association with NR2B negative allosteric modulating properties.

FIELD OF THE INVENTION

The present invention relates to novel 4-pyridinylmethyl-morpholinederivatives processes for their preparation, pharmaceutical compositionscontaining them and their use in therapy, particularly in the treatmentor prevention of conditions having an association with NR2B negativeallosteric modulating properties. The compounds of the invention showNR2B negative allosteric modulating properties.

BACKGROUND OF THE INVENTION

Extensive studies over the past twenty years have indicated thatN-methyl-D-aspartate receptors (NMDA) play a relevant role inAlzheimer's disease, Parkinson's disease, dyskinesia, stroke, motorneuron disease, psychosis, epilepsy, anxiety, schizophrenia and pain.

The non-selective NMDA receptor antagonist ketamine, (racemic as well asthe S enantiomer), a medication mainly used for starting and maintaininganaesthesia, has demonstrated over the last years clinical efficacy intreating major depressive disorder (MDD) at subanaesthetic doses(Murrough et al. 2013, Am J Psychiatry. 170: 1134; Singh et al. 2016,Biol Psychiatry. 80: 424). More precisely, ketamine elicits a rapidonset of efficacy which lasts several days in MDD patientsinsufficiently responding to standard drug therapy (Berman et al. 2000.Biol Psychiatry 47:351, Serafini et al. 2014. Curr.Neuropharmacol.12:444). However, non-selective NMDA receptor antagonistshave a range of undesirable effects which limit their application. Inparticular dissociative and psychogenic side effects are prominent forthe non-selective NMDA receptor antagonists such as ketamine (Krystal etal. 1994. Arch. Gen. Psychiatry 51:199). In the early 1990s, it wasfound that multiple NMDA receptor subtypes exist, which containdifferent NR2(A-D) subunits (Paoletti et al., 2013 Nat Rev. Neurosci14:383). More recently, NR2B subtype selective NMDA receptor negativeallosteric modulators (NR2B NAM) have raised interest and have shownpotential in a wide range of clinical indications, such as attention,emotion, mood, and pain, as well as being involved in a number ofdifferent human disorders (Mony et. al. 2009. Br. J. Pharmacol.157:1301; Chaffey et al., Current Anaesthesia & Critical Care 19, 183).In particular, NR2B NAM have also demonstrated antidepressant efficacyin the early stage of clinical trials (Preskorn et al. 2008. J ClinPsychopharmacol 70:58). Preclinical studies using NR2B NAM as well asapplying various transgenic mice strains have shown that NR2B containingNMDA-receptors are mediating the positive effect of ketamine in e.g. theForced Swim Test (Miller et al. 2014 eLife 3:e03581; Kiselycznyk et al.2015, Behav Brain Res, 287:89). Furthermore, selective NR2B NAM haveadvantages over unselective NMDA receptor antagonists, such as ketamine,due to greatly diminished dissociative and psychotomimetic side effects(Jimenez-Sanchez et al. 2014. Neuropsychopharmacology 39:2673). NR2B NAMdescribed to date have exhibited drawbacks with regard to their receptorpharmacology and/or to other drug properties which have limitedpotential use in human drug therapy (Taylor, et al., 2006, ClinPharmacokinet.45: 989;Addy et al. 2009 J of Clinical Pharmacology49:856)).

WO2015/130905 discloses compounds of formula (I)

that are inhibitors of Nav1.6 useful in the treatment of multiplesclerosis, polyneuritis, multiple neuritis, amyotrophic lateralsclerosis, Alzheimer's disease or Parkinson's disease. WO2015/130905discloses the specific examples 100, 105, 106 and 107 in which ring Bcorresponds to a meta-disubstituted phenyl ring.

WO2015/130905 reports specific examples 100, 105, 106 and 107 to be weakNav1.6 inhibitors (Nav 1.6 blockage of examples 100, 105 and 107 at 1-5μM, and Nav 1.6 blockage of example 106 at >5 μM).

SUMMARY OF THE INVENTION

The present invention provides novel 4-Pyridinylmethyl-morpholinederivatives of formula A

in which

-   X₁ is N and X₂ is CH, or-   X₁ is CH and X₂ is N,-   R¹ represents methyl, ethyl, propyl, iso-propyl, cyclopropyl,    H₃C—CH₂—CH₂—CH₂—, cyclobutyl;-   R² represents phenyl which is optionally substituted with 1, 2 or 3    substituents selected from the group consisting of fluoro, chloro,    methyl, ethyl, cyclopropyl;-   or a salt thereof, particularly a pharmaceutically acceptable salt    thereof.

According to another embodiment, the present invention comprisescompounds of the general formula A1 or formula A2

in which R¹ and R² have the same meaning as defined in any of thepreceding embodiments.

In another embodiment, in the general formula A, A1, A2, X₁, X₂, R² havethe same meaning as defined in any of the preceding embodiments, and

R¹ represents methyl.

In another embodiment, in the general formula A, A1, A2, X₁, X₂, R¹ havethe same meaning as defined in any of the preceding embodiments, and

R² represents

Compounds of the present invention are generically encompassed byformula (I) of WO2015/130905. The compounds of the present inventiondiffer structurally from the examples 100, 105, 106 and 107 explicitlydisclosed in WO2015/130905 in that they contain a para-disubstitutedpyridyl substructure in place of the meta-disubstituted phenyl ring.

The structural differences unexpectedly result in potent NR2B negativeallosteric modulators (see Table 1), whereas the specific examples 100,105, 106 and 107 of WO2015/130905 do not show any activity on theNR1-NR2B ion channel (see Table 2). Furthermore, compounds of thepresent invention do not inhibit Nav 1.6 at concentrations at whichspecific examples 100 and 105 of WO2015/130905 inhibit Nav 1.6 (5 μM;see Tables 3 and 4).

Further, the compounds of the present invention show good membranepermeability and is no in vitro efflux (see Table 5 for MDCK assay MDR1(P-gp)). Therefore, compounds of the present invention are expected toshow a favorable brain penetration which is required for efficacious CNSmedicaments.

The MDCK assays provide information on the potential of a compound topass the blood brain barrier. Permeability measurements acrosspolarized, confluent MDCK-MDR1 cell monolayers grown on permeable filtersupports are used as an in vitro absorption model: apparent permeabilitycoefficients (PE) of the compounds across the MDCK-MDR1 cell monolayersare measured (pH 7.4, 37° C.) in apical-to-basal (AB) andbasal-to-apical (BA) transport direction. The AB permeability (PEAB)represents drug absorption from the blood into the brain and the BApermeability (PEBA) drug efflux from the brain back into the blood viaboth, passive permeability as well as active transport mechanismsmediated by efflux and uptake transporters that are expressed on theMDCK-MDR1 cells, predominantly by the overexpressed human MDR1.Identical or similar permeabilities in both transport directionsindicate passive permeation (PEBA/PEAB≤1), vectorial permeability pointsto additional active transport mechanisms. Higher PEBA than PEAB(PEBA/PEAB>5) indicates the involvement of active efflux mediated byMDR1, which might compromise the goal to achieve sufficient brainexposure. Therefore, this assay provides valuable support for selectionof compounds applicable for further in vivo testing. High permeabilitynot limited by efflux at the blood brain barrier is a favorablecharacteristic for compounds that are to be used for drugs actingprimarily in the CNS.

Further, the compounds of the present invention are metabolically stablein human liver microsomes (see Table 6, metabolic stability). Therefore,compounds of the present invention are expected to have a favorable invivo clearance and thus the desired duration of action in humans.

Stability in human liver microsomes refers to the susceptibility ofcompounds to biotransformation in the context of selecting and/ordesigning drugs with favorable pharmacokinetic properties. The primarysite of metabolism for many drugs is the liver. Human liver microsomescontain the cytochrome P450s (CYPs), and thus represent a model systemfor studying drug metabolism in vitro Enhanced stability in human livermicrosomes is associated with several advantages, including increasedbioavailability and adequate half-life, which can enable lower and lessfrequent dosing of patients. Thus, enhanced stability in human livermicrosomes is a favorable characteristic for compounds that are to beused for drugs.

Consequently, compounds of the present invention must be more viable forhuman use.

The objective technical problem is thus to provide potent and selectiveNR2B negative allosteric modulators.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows Tetracaine inhibition of Nav1.6.

FIG. 2 shows the inhibition of evoked currents in a concentration anduse dependent manner using Lidocaine as reference compound.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel 4-Pyridinylmethyl-morpholinederivatives of general formula A that unexpectedly are potent andselective negative allosteric modulators of NR2B.

Another aspect of the invention refers to compounds according to formulaA as potent and selective NR2B negative allosteric modulators havinghigh membrane permeability and no in vitro efflux.

Another aspect of the invention refers to compounds according to formulaA as potent and selective NR2B negative allosteric modulators havinghigh metabolic stability in human liver microsomes.

Another aspect of the invention refers to compounds according to formulaA as potent and selective NR2B negative allosteric modulators havinghigh membrane permeability, no in vitro efflux, and high metabolicstability in human liver microsomes.

Another aspect of the invention refers to pharmaceutical compositions,containing at least one compound according to formula A optionallytogether with one or more inert carriers and/or diluents.

A further aspect of the present invention refers to compounds accordingto formula A, for the use in the prevention and/or treatment ofdisorders associated with NR2B negative allosteric modulators.

Another aspect of the invention refers to processes of manufacture ofthe compounds of the present invention.

Preparation

The following schemes shall illustrate generally how to manufacture thecompounds according to general formula A and the correspondingintermediate compounds by way of example. The abbreviated substituentsmay be as defined above if not defined otherwise within the context ofthe schemes.

Scheme 1 illustrates the synthesis of pyridine derivatives of generalformula A2.The first step is a nucleophilic substitution of asubstituted phenol derivative R2-OH and6-chloro-pyridine-3-carbaldehyde; the last step is represented by areductive amination involving the aldehyde and a slight excess of anamide derivative of the (S)-Morpholine-2-carboxylic acid obtained byreacting (S)-Morpholine-2-carboxylic acid methyl ester with thecorresponding amine R1-NH₂.

The described synthetic approach can be used also for gram scalesynthesis applying different purification techniques such ascrystallization or column chromatography.

Scheme 2 illustrates the synthesis of pyridine derivatives of generalformula A1.The first step is a nucleophilic substitution of asubstituted phenol derivative R2-OH and5-Fluoro-pyridine-2-carbaldehyde; the last step is represented by areductive amination involving the aldehyde and a slight excess of anamide derivative of the (S)-Morpholine-2-carboxylic acid obtained byreacting (S)-Morpholine-2-carboxylic acid methyl ester with thecorresponding amine R1-NH₂.

The described synthetic approach can be used also for gram scalesynthesis applying different purification techniques such ascrystallization or column chromatography.

General Definitions

Terms not specifically defined herein should be given the meanings thatwould be given to them by one skilled in the art in light of thedisclosure and the context. NR2B ion channel should be understood asNMDA receptor containing the NR2B protein.

In case a compound of the present invention is depicted in form of achemical name as well as a formula, the formula shall prevail in case ofany discrepancy.

An asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule or to the substituent to which it isbound as defined.

The term “substituted” as used herein means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's viable valencenumber is not exceeded, and that the substitution results in a stablecompound.

Stereochemistry:

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompassrotamers, tautomers and all stereo, optical and geometrical isomers(e.g. enantiomers, diastereoisomers, E/Z isomers etc.) and racematesthereof, as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereoisomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist.

Salts:

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings without excessive toxicity, irritation,allergic response, or other problem or complication, and commensuratewith a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound forms a salt or acomplex with an acid or a base.

-   Examples for acids forming a pharmaceutically acceptable salt with a    parent compound containing a basic moiety include mineral or organic    acids such as benzenesulfonic acid, benzoic acid, citric acid,    ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid,    hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic    acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid,    phosphoric acid, salicylic acid, succinic acid, sulfuric acid or    tartaric acid.-   Examples for cations and bases forming a pharmaceutically acceptable    salt with a parent compound containing an acidic moiety include Na⁺,    K⁺, Ca²⁺, Mg²⁺, NH₄ ⁺, L-arginine, 2,2′-iminobisethanol, L-lysine,    N-methyl-D-glucamine or tris(hydroxymethyl)-aminomethane.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha sufficient amount of the appropriate base or acid in water or in anorganic diluent like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile, or a mixture thereof. Salts of other acids than thosementioned above which for example are useful for purifying or isolatingthe compounds of the present invention (e.g. trifluoroacetate salts)also comprise a part of the invention.

Biological Assays and Data

List of Abbreviations

-   DMEM Dulbecco's Modified Eagle's Medium-   FBS fetal Bovine Serum-   FLIPR fluorometric imaging plate reader-   HEK293 cell line derived from human embryonic kidney cells-   HEPES hydroxyethyl-piperazineethane-sulfonic acid buffer-   IC50 half maximal inhibitory concentration-   MDCK Madin-Darby canine kidney-   MDR1 Multi drug resistance protein 1-   P-gp p-Glycoprotein-   SEM standard error mean-   EGTA ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic    acid, also known as egtazic acid

In-Vitro Effect:

Determination of In Vitro Pharmacological Activity

The activity of the compounds of the invention may be demonstrated usingthe following in vitro NMDA NR1/NR2B cell assays:

Method:

A human HEK293 cell line with tetracyclin-inducible expression of NMDANR1/NR2B receptor was used as a test system for compound efficacy andpotency. The cell line was purchased from ChanTest, Catalog #CT6121.Compound activity was determined by measuring the effect of compounds onintracellular calcium concentration induced by glycine/glutamate agonismin a FLIPRtetra system (Molecular Devices).

Cell Culture:

The cells were obtained as frozen cells in cryo-vials and stored untiluse at −150° C. Cells were grown in culture medium (DMEM/F12, 10% FBS, 5μg/mL Blasticidin, 150 μg/mL Zeozin, 500 μg/mL Geneticin). It isimportant that density does not exceed 80% confluence. For sub-culturingthe cells were detached from flasks by Versene. For the assay, cellswere detached, washed twice with induction medium (DMEM/F12 withoutglutamine, 10% FBS, 2 μg/mL Tetracycline, 2 mM Ketamine) and seeded to384 well pure coat amine plates (Becton Dickinson, 50000 cells per wellin 50 μl) 48 h prior to assay in induction medium.

Compound Preparation

The test compounds were dissolved in 100% DMSO at a concentration of 10mM and in a first step diluted in DMSO to a concentration of 5 mM,followed by serial dilution steps in 100% DMSO. Dilution factor andnumber of dilution steps may vary according to needs. Typically 8different concentrations by 1:5 dilutions were prepared in duplicate,further intermediate dilutions (1:37.5) of the substances were carriedout with aqueous assay buffer (137 mM NaCl, 4 mM KCl, 1.8 mM CaCl₂, 10mM HEPES, 10 mM Glucose, pH 7.4) resulting in a compound concentration 3times above the final test concentration and DMSO at 2.7% resulting in0.9% final DMSO concentration in the assay.

FLIPR Assay:

At the assay day cells were washed 3× with assay buffer (as describedabove), 10 μL buffer remained in the wells after washing. 10 μL Ca kitloading buffer (AAT Bioquest; prepared from the kit containing thefollowing components: Component A: Fluo-8 NW dissolved in 200 μL DMSOand 20 μl of this solution are mixed with 10 ml buffer prepared out ofcomponent B and C , Component B: 10X Pluronic® F127 Plus diluted 1:10 incomponent C, Component C: HHBS (Hanks with 20 mM Hepes) was added to thecells and the plates were incubated with lid for 60 minutes at roomtemperature. 20 μl assay buffer containing 60 μM glycine (20 μM final)and 3 μM glutamate (1 μM final) was added to column 1-23, column 24 gotassay buffer without glycine/glutamate to serve as negative unstimulatedcontrol. Fluorescence (indicating the calcium influx as a result of theNR1/NR2B ion channel activation) was read on the FLIPRtetra device for60 seconds to monitor the glutamate induced effects. After 2 minutes 20μL of compound dilution prepared as described above or controls (row1-22) in assay buffer were carefully added to the wells. Fluorescencewas read on the FLIPR tetra device for additional 6 minutes to monitorthe compound induced effects after activation by agonists. The averageof 2 measurements at 5 minutes and 5 mM 10 seconds after compoundaddition is calculated and further used for IC50 calculations. Eachassay microtiter compound dilution plate contained wells (in column 23or 24) with DMSO controls instead of compound as controls forglycine/glutamate induced fluorescence (high controls) and wells with 1μM of a reference NR2B NAM as low controls (Compound 22; reference:Layton, Mark E et al, ACS Chemical Neuroscience 2011, 2(7), 352-362).

Data Evaluation and Calculation:

The output file of the reader contains the well number and measuredaverage fluorescence units. For data evaluation and calculation, themeasurement of the low control was set as 0% control and the measurementof the high control was set as 100% control. The IC50 values werecalculated using the standard 4 parameter logistic regression formula.Calculation: [y=(a−d)/(1+(x/c){circumflex over ( )}b)+d], a=low value,d=high value; x=conc M; c=IC50 M; b=slope.

NR2B negative allosteric modulators covered by general structure A andexhibiting a low IC₅₀ value are preferred.

TABLE 1 In vitro NR2B affinity of the compounds of the present inventionas obtained in the FLIPR assay. Example number IC₅₀ [nM] 11 103 12 11713 442 14 198 15 69 16 205 17 188 19 199 29 194 30 454 31 275 32 255 33366 34 133 35 457 36 353 37 203 38 419 39 282 40 452 41 286

TABLE 2 In vitro NR2B affinity of the closest prior art compounds(examples 100, 105, 106 and 107 in WO2015/130905) as obtained in thesame FLIPR assay as compounds in Table 1. Example number inWO2015/130905 IC50 [nM] 100 >8887 105 >9261 106 >9255 107 >9257

Determination of Nav 1.6.Inhibition

Equipment:

IonWorks Quattro electrophysiological platform

Compound Plate Preparation

The compounds were prepared in DMSO at 300× the final assayconcentrations of 1 and 5 μM.

The 300× DMSO stock solutions were transferred into assay plates where 2μl per well of each 300× stock solution were placed. All assay plateswere stored at −80° C. until the day of assay.

On the day of the assay, the appropriate assay plate was thawed at roomtemperature, centrifuged, and 198 μl of external recording solution wasadded and mixed thoroughly. This provided a 1:100 dilution. A further1:3 dilution occurred upon addition to the cells in the IonWorks Quattroelectrophysiological platform, giving a 1:300 dilution in total. On eachassay plate, at least 8 wells were reserved for vehicle control (0.3%DMSO) and at least 8 wells for each positive control specific to thecell line tested. The positive controls were tested at a maximalblocking and an approximate IC50 concentration. As positive controlLidocaine at concentrations of 30 and 1000 μM was used.

Electrophysiological Recording Solutions

The solutions for recording Nav1.6 currents were as follows:

External Recording Solution

NaCl 137 mM

KCl 4 mM

MgCl₂ 1 mM

CaCl₂ 1.8 mM

HEPES 10 mM

Glucose 10 mM

pH 7.3 (titrated with 10M NaOH)

Internal Recording Solution

CsF 90 mM

CsCl 45 mM

HEPES 10 mM

EGTA 10 mM

pH 7.3 (titrated with 1M CsOH)

Amphotericin B was used to obtain electrical access to the cell interiorat a final concentration of 200 μg/ml in internal recording solution.

Experimental Protocols & Data Analysis

Nav1.6 Experimental Protocol

State-dependent inhibition: Sodium channels when held at depolarizedpotential or long test pulse, the channels open and inactivate and thenstay inactivated until the membrane potential is stepped back tohyperpolarized potentials, when the inactivated channels recover frominactivation into closed state. An example is Tetracaine inhibition(FIG. 1), which is much stronger at depolarized potentials than athyperpolarized potential.

Nav1.6 Data Analysis

Cells were held at −120 mV. In order to completely inactivate the sodiumchannels (pulse 1), the cells were pulsed to +0 mV for 2500 ms andstepped back to −120 mV for 10 ms (to completely recover frominactivation, however channels that had drugs bound to them will notrecover from inactivation) before stepping to +0 mV for 20 ms (pulse 2).

IonChannel Profiler Data Filters

Data Filter Platform Criteria Seal Quality IonWorks Quattro >30 MΩ SealDrop IonWorks Quattro <50% Seal Drop (Seal Pre-Compound/ Seal PostCompound) Current Amplitude IonWorks Quattro >200 pA

Assay Control Results

Both the positive and vehicle control data associated with each cellline assayed are shown below as an example. The mean is shown for eachpositive and negative control as solid symbol with the total number ofindividual well replicates given next to the solid symbol. In addition,the individual data of each well are shown on the graph as open symbolsso that the variation about the mean value can be readily assessed.These data are provided to aid in determining whether a compound hasactivities on the ion channel relative to the control data and providesan indication of assay variability and accordingly is used to judge theeffect size of a compound-specific effect that can be detected.

Shown below are the assay controls for the Nav1.6 IonWorks Quattroassay. Lidocaine, a Nav1.6 reference compound, inhibited evoked currentsin a concentration and use dependent manner as predicted (FIG. 2).

-   -   In FIG. 2, a Post/Pre value of 1.0 corresponds to 0% inhibition,        a Post/Pre value of 0.0 corresponds to 100% inhibition. To        illustrate the variation of the assay, both example 106 of        WO2015/130905 showing 14% inhibition of Nay 1.6 at 5 μM        (normalized, see Table 3) and example 19 of the present        invention showing −6.3% inhibition of Nav 1.6 at 5 μM        (normalized, see Table 4), respectively, are within the        variation of the assay when compared to assay control data, and        are therefore not showing any significant inhibition of the Nav        1.6 channel at 5 μM.

Tables 3 and 4 show the normalized percentage inhibition of Nav1.6channel The normalized data show the compound data normalized to vehiclecontrol (0% inhibition) and maximal inhibition control (100%inhibition); maximum inhibition at P1 by 1000 μM lidocaine (notnormalized) was ranging from 46.4% to 47.2% across the experiments. (seealso the figure Assay Control Results above).

TABLE 3 Normalized in vitro Nav 1.6 inhibition of the closest prior artcompounds (examples 100, 105, 106 and 107 in WO2015/130905) as obtainedin the same electrophysiology assay as compounds in Table 4(concentrations: 1 μM and 5 μM). Example number in Normalized NormalizedPercentage Percentage WO2015/ % inhibition % inhibition SEM at SEM at130905 at 1 μM at 5 μM 1 μM 5 μM 100 2.2 37.8 6.2 8.4 105 18.2 68 2.64.1 106 −0.7 14 1.6 0.4 107 −8.5 13.1 3.9 2.8

TABLE 4 Normalized in vitro Nav 1.6 inhibition of the compounds of thepresent invention as obtained in the same electrophysiology assay asprior art compounds in Table 3 (concentrations: 1 μM and 5 μM).Normalized Normalized Percentage Percentage Example % inhibition %inhibition SEM at SEM at number at 1 μM at 5 μM 1 μM 5 μM 11 4.2 −3.62.7 3.9 12 5.1 10.2 3.9 0.7 13 −3.1 −1.8 1.0 6.6 14 0.7 0.4 — 2.5 15−17.4 −1.4 5.5 3.4 16 −0.5 7.1 2.1 4.4 17 22 −4.3 4.3 4.2 19 5.2 −6.31.4 — 29 1.8 3.0 3.4 2.5 30 7.6 6.8 0.7 3.6

NR2B negative allosteric modulators covered by general structure A whichare not showing any significant Nav1.6 inhibition are preferred.

The compounds of the present invention do not show any significantinhibition of the Nav 1.6 channel at 1 and 5 μM, respectively (see Table4 and Assay Control Results), whereas examples 100 and 105 ofWO2015/130905 show 37.8% and 68% inhibition of Nav 1.6 at 5 μM (seeTable 3). Examples_106 and 107 of WO2015/130905 do not show anysignificant inhibition of the Nav 1.6 channel at 1 and 5 μM,respectively (i.e. inhibition is within assay variability, see Table 3and Assay Control Results).

MDCK Assay P-gp

Apparent permeability coefficients (Papp) of the compounds across theMDCK-MDR1 monolayers (MDCKII cells transfected with human MDR1 cDNAexpression plasmid) are measured in apical-to-basal (AB) andbasal-to-apical (BA) direction. MDCK-MDR1 cells (6×10⁵ cells/cm²) areseeded on filter inserts (Corning, Transwell, polycarbonate, 0.4 μm poresize) and cultured for 9 to 10 days. Compounds dissolved in DMSO stocksolution (1-20 mM) are diluted with HTP-4 aqueous buffer (128.13 mMNaCl, 5.36 mM KCl, 1 mM MgSO₄, 1.8 mM CaCl₂, 4.17 mM NaHCO₃, 1.19 mMNa₂HPO₄, 0.41 mM NaH₂PO₄, 15 mM HEPES, 20 mM glucose, pH 7.4)supplemented with 0.25% BSA to prepare the transport solutions (finalconcentration: 1 or 10 μM, final DMSO<=0.5%). The transport solution isapplied to the apical or basolateral donor side for measuring A-B or B-Apermeability, respectively. The receiver side contains HTP-4 buffersupplemented with 0.25% BSA. Samples are collected at the start and endof experiment from the donor and at various time intervals for up to 2hours also from the receiver side for concentration measurement byHPLC-MS/MS (RapidFire High-throughput MS System (Agilent) coupled toQTrap 6500 (AB Sciex) or TSQ Vantage (Thermo Scientific)). Sampledreceiver volumes are replaced with fresh receiver solution. Efflux ratiois calculated dividing the Papp (b-a) values by the Papp (a-b) values.Results are shown in Table 5.

TABLE 5 Papp (a-b) mean efflux ratio Ex. [10−6 cm/s] PEBA/PEAB 11 72 0.612 80 0.7 13 45 1.0 14 92 0.4 15 42 0.7 16 51 0.7 17 67 0.6 19 75 0.7 2958 0.8 30 86 0.5 31 63 0.7 32 80 0.5 33 71 0.5 34 58 0.8

The experimental results above show that compounds of the presentinvention are potent NR2B NAMs having high membrane permeability and noin vitro efflux anticipating excellent capability to cross the bloodbrain barrier.

Metabolic Stability

The metabolic degradation of the test compound was assayed at 37° C.with pooled human liver microsomes. The final incubation volume of 60 μlper time point contains TRIS buffer pH 7.6 at room temperature (0.1 M),magnesium chloride (5 mM aqueous solution), microsomal protein (1 mg/mLfor human) and the test compound at a final concentration of 1 μM.Following a short preincubation period at 37° C., the reactions wereinitiated by addition of betanicotinamide adenine dinucleotidephosphate, reduced form (NADPH, 1 mM), and terminated by transferring analiquot into acetonitril after different time points. Aftercentrifugation (10000 g, 5 min), an aliquot of the supernatant wasassayed by HPLC-MS/MS as described above for the MDCK assay P-gp for theamount of parent compound. The half-life was determined by the slope ofthe semi-logarithmic plot of the concentration-time profile. Results areshown in Table 6.

TABLE 6 Half-life - t½ [min] Ex. human liver microsomes 11 >130 12 >13013 >130 14 >130 15 >130 16 >130 17 >130 19 >130 29 >130 30 >130 31 >13032 >130 33 >130 34 >130

The experimental results above show that compounds of the presentinvention are potent NR2B NAMs having high stability in human livermicrosomes.

The present invention provides compounds according to formula A thatunexpectedly result in a favorable combination of the following keyparameters:

-   -   1) potent and selective negative allosteric modulation of NR2B,    -   2) high stability in human liver microsomes, and    -   3) high permeability and no in vitro efflux at MDCK-MDR1 cell        transporters.

Pharmaceutical Composition

Suitable preparations for administering the compounds of the presentinvention will be apparent to those with ordinary skill in the art andinclude for example tablets, pills, capsules, suppositories, lozenges,troches, solutions, syrups, elixirs, sachets, injectables, inhalatives,powders, etc. The content of the pharmaceutically active compound(s) mayvary in the range from 0.1 to 95 wt.-%, preferably 5.0 to 90 wt.-% ofthe composition as a whole.

Suitable tablets may be obtained, for example, by mixing a compound ofthe present invention with known excipients, for example inert diluents,carriers, disintegrants, adjuvants, surfactants, binders and/orlubricants and pressing the resulting mixture to form tablets.

Use in Treatment/Method of Use

Human therapeutic applications of NR2B NAM have been summarized inreviews by Traynelis et al. (Traynelis et al., Pharmacology Reviews,2010, 62:405), Beinat et al. (Beinat et al., Current MedicinalChemistry, 2010, 17:4166) and Mony et al. (Mony et al., British J.Pharmacology, 2009, 157:1301).

The present invention relates to compounds which are useful in thetreatment of psychiatric disorders, diseases and conditions whereinnegative allosteric modulation of NR2B is of therapeutic benefit,including: (1) mood disorders and mood affective disorders; (2)schizophrenia spectrum disorders; (3) neurotic, stress-related andsomatoform disorders including anxiety disorders; (4) disorders ofpsychological development; (5) behavioral syndromes associated withphysiological disturbances and physical factors; (6) substance-relatedand addictive disorders; (7) disease associated with symptoms ofnegative and positive valence; (8) pain; (9) cerebrovascular diseases;(10) episodic and paroxysmal disorders; (11) neurodegenerative diseases.

In view of their pharmacological effect, compounds of the presentinvention are suitable for use in the treatment of a disorder, diseaseor condition selected from the list consisting of

(1) treatment of mood disorders and mood affective disorders includingbipolar disorder I depressed, hypomanic, manic and mixed form; bipolardisorder II; depressive disorders, such as single depressive episode orrecurrent major depressive disorder, minor depressive disorder,depressive disorder with postpartum onset, depressive disorders withpsychotic symptoms; major depressive disorder with or withoutconcomitant anxious distress, mixed features, melancholic features,atypical features, mood-congruent psychotic features, mood-incongruentpsychotic features, catatonia.

(2) treatment of mood disorders belonging to the schizophrenia spectrumand other psychotic disorders including schizophrenia andschizoaffective disorder with associated negative and cognitivesymptoms.

(3) treatment of disorders belonging to the neurotic, stress-related andsomatoform disorders including anxiety disorders, general anxietydisorder, panic disorder with or without agoraphobia, specific phobia,social phobia, chronic anxiety disorders; obsessive compulsive disorder;reaction to sever stress and adjustment disorders, such aspost-traumatic stress disorder; other neurotic disorders such asdepersonalisation-derealisation syndrome.

(4) treatment of disorders of psychological development includingpervasive developmental disorders, including Asperger's syndrome andRett's syndrome, autistic disorders, childhood autism and overactivedisorder associated with mental retardation and stereotyped movements,specific developmental disorder of motor function, specificdevelopmental disorders of scholastic skills, attentiondeficit/hyperactivity disorder.

(5) treatment of behavioral syndromes associated with physiologicaldisturbances and physical factors including mental and behaviouraldisorders associated with the puerperium, including postnatal andpostpartum depression; eating disorders, including anorexia nervosa andbulimia nervosa and other impulse control disorders.

(6) treatment of disorders of substance-related and addicitivedisorders, which are is substance use disorders induced by alcohol,cannabis, hallucinogen, stimulant, hypnotic, tobacco.

(7) treatment of disease associated with symptoms of negative andpositive valence including anhedonia, sustained threat and loss,suicidal ideation.

(8) treatment of acute and chronic pain which is related to neuropathy,e.g. diabetic neuropathy or polyneuropathy, physiological processes andphysical disorders including e.g. low back pain, pain in the joints,disease of the musculoskeletal system and connective tissue, e.g.rheumatism, myalgia, nerve, nerve root and plexus disorders, e.g.phantom limb syndrome with pain, carpal tunnel syndrome.

(9) treatment of cerebrovascular diseases, e.g. intracerebral orsubararchnoid haemorrhage, cerbral infarction, stroke, occlusion andstenosis, cerebral atherosclerosis, cerebral amyloid angiopathy.

(10) treatment of episodic and paroxymal disorders, e.g. epilepsy.

(11) treatment of diseases which include forms of neurodegeneration,e.g. stroke, Alzheimer's disease and Huntingon's disease.

As used herein, unless otherwise noted, the terms “treating”,“treatment” shall include the management and care of a human subject orhuman patient for the purpose of combating a disease, condition, ordisorder and includes the administration of a compound of the presentinvention to prevent the onset of the symptoms or complications,alleviate the symptoms or complications, or eliminate the disease,condition, or disorder.

As used herein, unless otherwise noted, the term “prevention” shallinclude (a) reduction in the frequency of one or more symptoms; (b)reduction in the severity of one or more symptoms; (c) the delay oravoidance of the development of additional symptoms; and/or (d) delay oravoidance of the development of the disorder or condition.

According to another aspect, the present invention provides a compoundof formula A or a pharmaceutically acceptable salt thereof for use inthe treatment and/or prevention of the above mentioned conditions.

According to another aspect, the present invention provides a compoundof formula A according to any one of the preceding aspects characterizedin that the compound of formula A is used in addition to behaviouraltherapy, TMS (transcranial magnetic stimulation), ECT (electroconvulsivetherapy) and other therapies.

Combination Therapy

Compounds according to the present invention can be combined with othertreatment options known to be used in the art in connection with atreatment of any of the indications the treatment of which is in thefocus of the present invention.

According to another aspect, the present invention provides a compoundof formula A according to any one of the preceding aspects characterizedin that the compound of formula A is administered in addition totreatment with one or more antidepressant selected from the listconsisting of duloxetine, escitalopram, bupropion, venlafaxine,desvenlafaxine, sertraline, paroxetine, fluoxetine, vortioxetine,mirtazapine, citalopram, vilazodone, trazodone, amitriptyline,clomipramine, agomelatine, levomilnacipran, lithium, doxepin,nortriptyline. The term “antidepressant” shall mean any pharmaceuticalagent or drug which can be used to treat depression or diseasesassocaited with depressive symptoms.

According to another aspect, the present invention provides a compoundof formula A according to any one of the preceding aspects characterizedin that the compound of formula A is administered in addition totreatment with one or more antipsychotic selected from the listconsisting of aripiprazole, paliperidone palmitate, lurasidone,quetiapine, risperidone, olanzapine, paliperidone, brexpiprazole,clozapine, asenapine, chlorpromazine, haloperidol, cariprazine,ziprasidone, amisulpride, iloperidone, fluphenazine, blonanserin,aripiprazole lauroxil. The term “antipsychotic” shall mean anypharmaceutical agent or drug which can be used to treat diseasesassociated with psychotic or depressive symptoms.

According to another aspect, the present invention provides a compoundof formula A according to any one of the preceding aspects characterizedin that the compound of formula A is administered in addition totreatment with one or more psychostimulant selected from the listconsisting of lisdexamfetamine, methylphenidate, amfetamine,dexamfetamine, dexmethylphenidate, armodafinil, modafinil The term“psychostimulant” shall mean any pharmaceutical agent or drug which canbe used to o treat diseases like mood disorders, or impulse controldisorders.

According to another aspect, the present invention provides a compoundof formula A according to any one of the preceding aspects characterizedin that the compound of formula A is administered in addition totreatment with nootropics selected from the list consisting ofoxiracetam, piracetam, or the natural product St John's-wort.

According to another aspect, the present invention provides a compoundof formula A which is administered in addition to treatment with one ormore antidepressant, antipsychotic, psychostimulant, nootropics ornatural product according to any one of the preceding aspectscharacterized in that the combination of compound of formula A and oneor more antidepressant, antipsychotic, psychostimulant, nootropics ornatural product is used in addition to behavioural therapy, TMS(transcranial magnetic stimulation), ECT (electroconvulsive therapy) andother therapies.

EXPERIMENTAL SECTION

Abbreviations:

-   ACN acetonitrile-   APCI Atmospheric pressure chemical ionization-   Boc tert-butyloxycarbonyl-   CDI 1,1′-carbonyldiimidazole-   CO₂ Carbon Dioxide-   D day-   DA Diode Array-   DCM dichloromethane-   DIPE diisopropylether-   DIPEA diisopropylethylamine-   DMF dimethylformamide-   e.e. enantiomeric excess-   ESI electrospray ionization (in MS)-   EtOAc ethylacetate-   EtOH ethanol-   Ex. example-   h hour(s)-   HATU    O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate-   HPLC high performance liquid chromatography-   HPLC-MS coupled high performance liquid chromatography-mass    spectrometry-   M molar (mol/L)-   MeOH methanol-   min minute(s)-   MS mass spectrometry-   MW molecular weight-   NH3 ammonia-   PSI Pound per square inch-   rt room temperature-   R_(t) retention time-   scCO2 supercritical CO₂-   solv solvent-   TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin-layer chromatography-   SFC Supercritical fluid chromatography

Abbreviations within Spectral Data:

-   1H-NMR Proton nuclear magnetic resonance-   br broad-   δ chemical shift-   d doublet-   dd doublet of doublets-   dt doublet of triplets-   DMSO-d₆ hexa-deutero-dimethylsulfoxide-   H proton-   Hz Hertz (=1/second)-   J coupling constant-   m multiplet-   ppm parts per million-   q quartet-   s singlet-   t triplet-   td triplet of doublets

General Analytics.

All reactions were carried out using commercial grade reagents andsolvents. NMR spectra were recorded on a Bruker AVANCE IIIHD 400 MHzinstrument using TopSpin 3.2 p16 software. Chemical shifts are given inparts per million (ppm) downfield from internal referencetrimethylsilane in δ units. Selected data are reported in the followingmanner: chemical shift, multiplicity, coupling constants (J),integration. Analytical thin-layer chromatography (TLC) was carried outusing Merck silica gel 60 F254 plates. All compounds were visualized assingle spots using short wave UV light. Low resolution mass spectra wereobtained using a liquid chromatography mass spectrometer (LCMS) thatconsisted of an Agilent 1100 series LC coupled to a Agilent 6130quadrupole mass spectrometer (electrospray positive ionization).

Methods:

HPLC-MS methods:

Method 1

Method Name: Z003_S05 Device description: Agilent 1200 with DA- andMS-Detector Column: XBridge C18_3.0 × 30 mm_2.5 μm Column producer:Waters Description: Gradient/ Solvent % Sol Back Time [Water % Sol FlowTemp pressure [min] 0.1% NH₃] [Acetonitrile] [ml/min] [° C.] [PSI] 0.095.0 5.0 2.2 60.0 0.2 95.0 5.0 2.2 60.0 1.2 0.0 100.0 2.2 60.0 1.25 0.0100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0

Method 2

Method Name: Z011_S03 Device description: Agilent 1200 with DA- andMS-Detector Column: XBridge C18_3.0 × 30 mm_2.5 μm Column producer:Waters Description: Gradient/ Solvent % Sol Back Time [Water % Sol FlowTemp pressure [min] 0.1% NH₃] [Acetonitrile] [ml/min] [° C.] [PSI] 0.097.0 3.0 2.2 60.0 0.2 97.0 3.0 2.2 60.0 1.2 0.0 100.0 2.2 60.0 1.25 0.0100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0

Method 3

Method Name: Z017_S04 Device description: Agilent 1200 with DA- andMS-Detector Column: Sunfire C18_3.0 × 30 mm_1.8 μm Column producer:Waters Description: Gradient/ Solvent % Sol Back Time [Water % Sol FlowTemp pressure [min] 0.1% TFA] [Acetonitrile] [ml/min] [° C.] [PSI] 0.097.0 3.0 2.2 60.0 0.2 97.0 3.0 2.2 60.0 1.2 0.0 100.0 2.2 60.0 1.25 0.0100.0 3.0 60.0 1.4 0.0 100.0 3.0 60.0

Chiral SFC Analytical Methods:

Method 4: G_IG_IPA_NH₃_001

Method Name: G_IG_IPA_NH_(3 —)001 Device description: Agilent 1260 SFCwith DAD and MS Column: CHIRALPAK ® IG_4.6 × 250 mm_5 μm Columnproducer: Daicel Gradient/ Solvent % Sol Back Time % Sol [IPA Flow Temppressure [min] [scCO2] 20 mM NH₃] [ml/min] [° C.] [PSI] 0.0 95.0 5.0 4.040.0 2175.0 9.0 40.0 60.0 4.0 40.0 2175.0 10.0 40.0 60.0 4.0 40.0 2175.0

Method 5: G_IG_MeOH_NH₃_001

Method Name: G_IG_MeOH_NH_(3 —)001 Device description: Agilent 1260 SFCwith DAD and MS Column: CHIRALPAK ® IG_4.6 × 250 mm_5 μm Columnproducer: Daicel Gradient/ Solvent % Sol Back Time % Sol [MeOH Flow Temppressure [min] [scCO2] 20 mM NH₃] [ml/min] [° C.] [PSI] 0.0 95.0 5.0 4.040.0 2175.0 9.0 40.0 60.0 4.0 40.0 2175.0 10.0 40.0 60.0 4.0 40.0 2175.0

Method 6: G_C4_MeOH_NH₃_001

Method Name: G_C4_MeOH_NH_(3 —)001 Device description: Agilent 1260 SFCwith DAD and MS Column: LUX ® Cellulose-4 6 × 250 mm_5 μm Columnproducer: Phenomenex Gradient/ Solvent % Sol Back Time % Sol [MeOH FlowTemp pressure [min] [scCO2] 20 mM NH₃] [ml/min] [° C.] [PSI] 0.0 95.05.0 4.0 40.0 2175.0 9.0 40.0 60.0 4.0 40.0 2175.0 10.0 40.0 60.0 4.040.0 2175.0

Method 7: I_SA_20_MEOH_NH₃_001

Method Name: I_SA_20_IPA_NH_(3 —)001 Device description: Agilent 1260SFC with DAD and MS Column: CHIRAL ART ® Amylose SA_4.6 × 250 mm_5 μmColumn producer: YMC Gradient/ Solvent % Sol Back Time % Sol [ETOH FlowTemp pressure [min] [scCO2] 20 mM NH₃] [ml/min] [° C.] [PSI] 0.0 80.020.0 4.0 40.0 2175.0 10.0 80.0 20.0 4.0 40.0 2175.0

Method 8: I_IC_30_IPA_NH₃_001

Method Name: I_IC_30_IPA_NH_(3 —)001 Device description: Agilent 1260SFC with DAD and MS Column: Chiralpak ® IC_4.6 × 250 mm_5 μm Columnproducer: Daicel Gradient/ Solvent % Sol Back Time % Sol [MEOH Flow Temppressure [min] [scCO2] 20 mM NH₃] [ml/min] [° C.] [PSI] 0.0 70.0 30.04.0 40.0 2175.0 10.0 7.0 30.0 4.0 40.0 2175.0

Microwave equipment: Biotage Initiator⁺

Preparative HPLC Method for Purification:

Instrument: (Agilent 1100). Eluents: Water—NH₄OH 5% solution inWater—CH₃CN;

Flow: 50 ml/min; Temperature 60° C.; Column: XBridge C18.

Preparation of Intermediates:

Example 1a

(S)-Morpholine-2-carboxylic acid methyl ester hydrochloride (35.0 g; 193mmol) was mixed together with 400 ml of a 8M solution of Methylamine inEtOH. The reaction mixture was stirred at room temperature over 60hours. The solvent was removed under reduced pressure, THF (500 ml) andTEA (50 ml) were added and the reaction mixture stirred at roomtemperature during 12 hours. A precipitate was formed; the suspensionwas filtered via a glass filter and the filtrate solution was evaporatedunder reduced pressure. Obtained 23.5 g of the desired product as solid.

-   Example 1a: Chiral SFC Method: I_IC_30_IPA_NH₃_001.M R_(t) [min]:    3.72; e.e. 100% MS: 145 (M+H)⁺

Example 5a

6-Chloro-pyridine-3-carbaldehyde (1.50 g; 10.6 mmol) and2,4-difluoro-phenol (1.22 ml; 12.7 mmol) are dissolved in DMF (10 ml) ina microwave vial; K₂CO₃ (2.20 g; 15.9 mmol) is added and the reactionmixture is stirred at 110° C. during 30 minutes. The reaction mixture isthen partitioned between Ethyl Acetate (150 ml) and Water (80 ml); theorganic phase is separated and washed with a solution of K₂CO₃ (10% inwater) and the dried over Na₂SO₄. The crude product obtained afterevaporation of the solvent is purified by flash-chromatography (Eluent:Petrol Ether/Ethyl Acetate 4/1). Obtained 2.3g of the desired compound(content 70%) used as such in the next step.

-   Example 5a: HPLC-MS (Method): Z017_S04R_(t) [min]: 0.98 MS: 236    [M+H]⁺

Example 5b

Example 5b was synthesised in analogy to Example 5a. Starting materials:6-Chloro-pyridine-3-carbaldehyde (1.50 g; 10.6 mmol) and2-fluoro-4-methylphenol (1.38 ml; 12.7 mmol).

The crude obtained after work up was passed through a silica pad(Eluent: Petrol Ether/Ethyl Acetate 4/1). Obtained 1.60 g of the desiredcompound (content 50%) used as such in the next step.

-   Example 5b: HPLC-MS (Method): Z017_S04 R_(t) [min]: 1.02 MS: 232    [M+H]⁺

Example 5c

Example 5c was synthesised in analogy to Example 5a. Starting materials:6-Chloro-pyridine-3-carbaldehyde (1.50 g; 10.6 mmol) and2,-4-dimethylphenol (1.51 ml; 12.7 mmol).

The crude obtained after work up was passed through a silica pad(Eluent: Petrol Ether/Ethyl Acetate 4/1). Obtained 2.30 g of the desiredcompound (content 50%) used as such in the next step.

-   Example 5c: HPLC-MS (Method): Z017_S04 R_(t) [min]: 1.06 MS: 228    [M+H]⁺

Example 5d

Example 5d was synthesised in analogy to Example 5a. Starting materials:6-Chloro-pyridine-3-carbaldehyde (1.50 g; 10.6 mmol) and 4-fluoro-phenol(1.43 g; 12.7 mmol).

Obtained 1.40 g of the desired compound used as such in the next step.

-   Example 5d: MS: 218 [M+H]⁺; 250 HPLC-MS (Method): Z017_S04 R_(t)    [min]: 0.94 (M+H+MeOH)⁺

Example 5e

Example 5e was synthesised in analogy to Example 5a. Starting materials:6-Chloro-pyridine-3-carbaldehyde (1.50 g; 10.6 mmol) and2-fluoro-4-chloro-phenol (1.35 ml; 12.7 mmol).

Obtained 2.20 g of the desired compound (content 80-90%) used as such inthe next step.

-   Example 5e: MS: 252 and 254 [M+H]⁺; Isotopic HPLC-MS (Method):    Z017_S04 R_(t) [min]: 1.05 pattern for 1 Cl observed

Example 5f

Example 5f was synthesised in analogy to Example 5a. Starting materials:6-Chloro-pyridine-3-carbaldehyde (1.50 g; 10.6 mmol) and 4-chloro-phenol(1.63 g; 12.7 mmol).

Obtained 2.40 g of the desired compound used as such in the next step.

-   Example 5f: MS: 234 and 236 HPLC-MS (Method): Z017_S04 R_(t) [min]:    1.02 [M+H]⁺; Isotopic pattern for 1 Cl observed

Example 5g

Example 5g was synthesised in analogy to Example 5a. Starting materials:6-Chloro-pyridine-3-carbaldehyde (1.50 g; 10.6 mmol) and 2-chloro-phenol(1.29 ml; 12.7 mmol).

Obtained 2.40 g of the desired compound used as such in the next step.

-   Example 5g: MS: 234 and 236 HPLC-MS (Method): Z017_S04 R_(t) [min]:    0.99 [M+H]⁺; Isotopic pattern for 1 Cl observed

Example 5h

Example 5h was synthesised in analogy to Example 5a. Starting materials:6-Chloro-pyridine-3-carbaldehyde (1.50 g; 10.6 mmol) and 2-fluoro-phenol(1.13 ml; 12.7 mmol).

Obtained 2.00 g of the desired compound used as such in the next step.

-   Example 5h: HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.95 MS: 218    [M+H]⁺

Example 5i

Example 5i was synthesised in analogy to Example 5a. Starting materials:6-bromo-pyridine-3-carbaldehyde (1.89 g; 10.2 mmol) and 4-methyl-phenol(1.10 g; 10.2 mmol).

Obtained 2.40 g of the desired compound (content 70%) used as such inthe next step.

-   Example 5i: HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.95 MS: 214    [M+H]⁺

Example 5j

4-Fluoro-phenol (1.34 g; 12.0 mmol) was dissolved in DMSO (30 ml);potassium tert-butoxide (1.48 g; 13.2 mmol) was added at roomtemperature and the mixture was stirred for 1 h at room temperature.5-Fluoro-2-formyl pyridine (1.50 g; 12.0 mmol) was then added and thereaction mixture was stirred at room temperature during 16 hours. 200 mlof a 1/1 mixture Dietyl ether/Ethyl Acetate was added followed by 70 mlof water. The phases were separated and the organic phase washed oncemore with water (20 ml). The organic phase was then dried over Na₂SO₄;the residue obtained after evaporation of solvents was purified byflash-chromatography employing as eluent Petrol Ether/Ethyl Acetate(ratio: 7/3). Obtained 1.80 g.

-   Example 5j: HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.90 MS: 218    [M+H]⁺

Example 5k

5-Fluoro-2-formyl pyridine (0.25 g; 2.00 mmol) and Cs₂CO₃ (0.98 g; 3.00mmol) were suspended in DMF (10 ml); 2,4-difluoro-phenol (0.31 g; 2.40mmol) was added and the reaction mixture was stirred at 80° C. during 3hours. Acetonitrile (20 ml) was added and the mixture was filteredbefore being purified via preparative HPLC. Obtained 0.25 g of thedesired compound.

-   Example 5k: HPLC-MS (Method):): Z011_S03;R_(t) [min]: 0.96 MS: 236    [M+H]⁺

EXAMPL 5l

Example 5l was synthesised in analogy to example 5k. Starting materials:5-Fluoro-2-formyl pyridine (0.25 g; 2.00 mmol) and4-chloro-2-fluoro-phenol (0.26 ml; 2.40 mmol). Obtained: 0.35 g of thedesired product.

-   Example 5l : MS: 252 and 254 [M+H]⁺; HPLC-MS (Method):): Z011_S03;    Rt [min]: 1.03 Isotopic pattern for 1 Cl observed

Example 5m

Example 5m was synthesised in analogy to example 5k. Starting materials:5-Fluoro-2-formyl pyridine (0.25 g; 2.00 mmol) and 2-fluoro-phenol (0.21ml; 2.40 mmol).

Obtained: 0.23 g of the desired product.

-   Example 5m: HPLC-MS (Method):): Z011_S03: Rt [min]: 0.94 MS: 218    [M+H]⁺

Example 5n

Example 5n was synthesised in analogy to example 5k. Starting materials:5-Fluoro-2-formyl pyridine (0.25 g; 2.00 mmol) and2-fluoro-4-methyl-phenol (0.30 g; 2.40 mmol).

Obtained: 0.34 g of the desired product.

-   Example 5n: HPLC-MS (Method): Z011_S03: R_(t) [min]: 1.02 MS: 232    [M+H]⁺

Example 5o

5-Fluoro-2-formylpyridine (0.50 g; 4.00 mmol) and Phenol (0.45 g; 4.80mmol) were dissolved in DMF (8 nal); Cs₂CO₃ (1.43 g; 4.40 mmol) wasadded and the reaction mixture was stirred at 80° C. during 16 hours.The reaction mixture was then partitioned between ethyl acetate (80 ml)and water (40 ml); the organic phase was separated and dried overNa₂SO₄. The crude product obtained after evaporation of the solvent wasdiluted with MeOH/H2O (10 mL), filtered and purified by preparativeHPLC. Obtained 216 mg of the desired compound.

-   Example 5o: HPLC-MS (Method): Z017_S04: R_(t) [min]: 0.94 MS: 200    [M+H]⁺

Example 5p

6-Chloro-pyridine-3-carbaldehyde (1.50 g; 10.6 mmol) and Phenol (1.20 g;12.7 mmol) were dissolved in DMF (10 ml) in a microwave vial; K₂CO₃(2.20 g; 15.9 mmol) was added and the reaction mixture was stirred at110° C. during 30 minutes. The reaction mixture was diluted with water(50 ml) and the obtained precipitate was filtered off, washed with waterand dried in the air. Obtained 1.38 g of the desired compound.

-   Example 5p: HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.93 MS: 200    [M+H]⁺

Example 5q

6-Chloro-pyridine-3-carbaldehyde (1.50 g; 10.6 mmol) and2,6-difluoro-phenol (1.65 g; 12.7 mmol) were dissolved in DMF (10 ml) ina microwave vial; K₂CO₃ (2.20 g; 15.9 mmol) was added and the reactionmixture was stirred at 110° C. during 30 minutes. The reaction mixturewas then diluted with water (50 ml) and extracted with diethylether (70ml). The organic phase was separated and dried over Na₂SO₄. The crudeproduct obtained after evaporation was used as such in the next step.Obtained 2.30 g of the desired compound.

-   Example 5q: HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.98 MS: 236    [M+H]⁺

Example 5r

Example 5r was synthesised in analogy to example 5q. Starting materials:6-Chloro-pyridine-3-carbaldehyde (0.40 g; 2.83 mmol) and2-fluoro-6-methyl-phenol (0.39 g; 3.11 mmol). Obtained: 0.43 g of thedesired product (content 85%).

-   Example 5r: HPLC-MS (Method): Z017_S04: R_(t) [min]: 1.01 MS: 232    [M+H]⁺

Example 5s

5-Fluoro-2-formylpyridine (0.50 g; 4.00 mmol) and 2,6-Difluorophenol(0.62 g; 4.80 mmol) were dissolved in DMF (8 ml) in a microwave vial;Cs₂CO₃ (1.56 g; 4.80 mmol) was added and the reaction mixture wasstirred at 80° C. during 16 hours. The reaction mixture was diluted withwater (40 ml) and the obtained precipitate was filtered off, washed withwater and dried in the air. Obtained 0.73 g of the desired compound(content 85%).

-   Example 5s: HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.97 MS: 236    [M+H]⁺

Example 5t

6-Chloro-pyridine-3-carbaldehyde (1.50 g; 10.6 mmol) and2,5-difluoro-phenol (1.65 g; 12.7 mmol) were dissolved in DMF (10 ml) ina microwave vial; K₂CO₃ (2.20 g; 15.9 mmol) is added and the reactionmixture is stirred at 110° C. during 30 minutes. Water (50 ml) was addedand the reaction mixture stirred over 30 min. The precipitate obtainedafter filtration was washed a second time with water (20 ml), dried andused as such in the next step. Obtained 2.32 g of the desired compound.

-   Example 5t: HPLC-MS (Method): Z017_S04 R_(t) [min]: 0.98 MS: 236    [M+H]⁺

Example 5u

Example 5u was synthesised in analogy to Example 5t. Starting materials:6-Chloro-pyridine-3-carbaldehyde (1.50 g; 10.6 mmol) and2-chloro-5-difluoro-phenol (1.32 ml; 12.7 mmol). Obtained 2.4 g of thedesired cpd.

-   Example 5u: MS: 252 and 254 [M+H]⁺; HPLC-MS (Method): Z017_S04 R_(t)    [min]: 1.02 isotopic pattern of 1 Cl observed

Exemplary Embodiments Example 11

Example 1a (150 mg; content 70%; 0.45 mmol) and Example 5a (77.2 mg,0.54 mmol) were dissolved in DMF; Acetic acid (0.08 ml; 1.34 mmol) andDIPEA (0.11 ml; 0.63 mmol) were added and the reaction mixture wasstirred 30 min at 50° C.; NaBH(OAc)₃ (0.14 g; 0.67 mmol) was then addedand the mixture was the stirred 22 hours at room temperature. Thereaction mixture was then diluted with MeOH, filtered via a syringefilter and the obtained solution purified via preparative HPLC. Obtained120 mg of the io desired compound.

-   Example 11 HPLC-MS (Method): Z011_S03; R_(t) [min]: 0.93 MS: 364    [M+H]⁺R_(t) [min]: 1.83; Chiral SFC Method: I_SA_20_IPA_NH₃_001 e.e.    100% ¹H NMR (400 MHz, DMSO-d₆); δ ppm: 1.89 (t, J=10.81 Hz, 1H);    2.06-2.14 (m, 1H); 2.57 (d, J=4.71 Hz, 3H); 2.63 (br d, J=11.17 Hz,    1H); 2.88 (br d, J=11.17 Hz, 1H); 3.40-3.59 (m, 3H); 3.82-3.89 (m,    2H); 7.09-7.16 (m, 1H); 7.11 (d, J=8.44 Hz, 1H); 7.36-7.45 (m, 2H);    7.67 (q, J=4.42 Hz, 1H); 7.81 (dd, J=8.42, 2.37 Hz, 1H); 7.99 (d,    J=2.33 Hz, 1H).

Example 12

Example 12 was synthesised in analogy to example 11.

Starting materials: Example 5b (150 mg; content 50%; 0.32 mmol)+Example1a (56.1 mg; 0.39 mmol).

The crude was purified by preparative HPLC. Obtained 105 mg of thedesired compound.

-   Example 12 HPLC-MS Method : Z003_S05; R_(t) [min]: 1.11 MS: 360    [M+H]⁺R_(t) [min]: 2.39; e.e. Chiral SFC Method: I_SA_20_IPA_NH₃_001    100% ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.89 (t, J=10.81 Hz, 1H); 2.09    (br dd, J=11.47, 8.19 Hz, 1H); 2.33 (s, 3H); 2.54-2.59 (m, 3H);    2.60-2.65 (m, 1H); 2.88 (br d, J=11.28 Hz, 1H); 3.40-3.59 (m, 3H);    3.82-3.89 (m, 2H); 7.05 (t, J=10.04 Hz, 2H); 7.13-7.21 (m, 2H); 7.67    (br d, J=5.09 Hz, 1H); 7.78 (dd, J=8.42, 2.38 Hz, 1H); 7.97 (d,    J=2.35 Hz, 1H).

Example 13

Example 13 was synthesised in analogy to example 11.

Starting materials: Example 5c (200 mg; content 50%; 0.44 mmol)+Example1a (76.1 mg; 0.53 mmol).

The crude was purified by preparative HPLC. Obtained 119 mg of thedesired compound.

-   Example 13 HPLC-MS Method : Z011_S03; R_(t) [min]: 0.98 MS: 356    [M+H]⁺ R_(t) [min]: 2.95; Chiral SFC Method: I_SA_20_IPA_NH₃_001    e.e. 100% ¹H NMR (400 MHz, DMSO-d₆); δ ppm: 1.88 (t, J=10.81 Hz,    1H); 2.00-2.12 (m, 1H); 2.03 (s, 3H); 2.28 (s, 3H); 2.53-2.59 (m,    3H); 2.60-2.65 (m, 1H); 2.89 (br d, J=11.28 Hz, 1H); 3.39-3.59 (m,    4H); 3.80-3.90 (m, 2H); 6.92 (dd, J=8.27, 1.87 Hz, 2H); 7.02 (dd,    J=8.16, 2.22 Hz, 1H); 7.10 (s, 1H); 7.64-7.77 (m, 2H); 7.98 (d,    J=2.38 Hz, 1H).

Example 14

Example 14 was synthesised in analogy to example 11.

Starting materials: Example 5d (150 mg; 0.69 mmol)+Example 1a (119 mg;0.83 mmol). The crude was purified by preparative HPLC.

Obtained 149 mg of the desired compound.

-   Example 14 HPLC-MS Method : Z003_S05; R_(t) [min]: 1.05 MS: 346    [M+H]⁺R_(t) [min]: 2.23; Chiral SFC Method: : I_SA_20_IPA_NH₃_001    e.e. 100% ¹H NMR (400 MHz, DMSO-d₆); δ ppm: 1.89 (t, J=10.82 Hz,    1H); 2.11 (td, J=11.37, 3.33 Hz, 1H); 2.54-2.59 (m, 3H); 2.60-2.68    (m, 1H); 2.89 (dt, J=11.19, 2.12 Hz, 1H); 3.41-3.60 (m, 3H);    3.83-3.89 (m, 2H); 7.01 (d, J=8.40 Hz, 1H); 7.15-7.26 (m, 4H);    7.62-7.71 (m, 1H); 7.78 (dd, J=8.40, 2.39 Hz, 1H); 8.03 (s, 1H).

Example 15

Example 15 was synthesised in analogy to example 11.

Starting materials: Example 5e (150 mg; content 85%; 0.51 mmol)+Example1a (87.7 mg; 0.61 mmol). The crude was purified via preparative HPLC.Obtained 132 mg of the desired compound.

-   Example 15 MS: 380 and 382 HPLC-MS Method : Z003_S05; R_(t) [min]:    1.14 [M+H]⁺; isotopic pattern for 1 Cl observed Chiral SFC Method:    I_SA_20_IPA_NH₃_001 R_(t) [min]: 2.48; e.e. 100% ¹H NMR (400 MHz,    DMSO-d₆); δ ppm 1.89 (t, J=10.80 Hz, 1H); 2.06-2.14 (m, 1 H);    2.52-2.59 (m, 3H); 2.60-2.65 (m, 1H); 2.88 (dt, J=11.22, 2.13 Hz,    1H); 3.41-3.60 (m, 3H); 3.81-3.90 (m, 2H); 7.13 (d, J=8.40 Hz, 1H);    7.31-7.41 (m, 2H); 7.60 (dd, J=10.46, 2.40 Hz, 1H); 7.64-7.70 (m,    1H); 7.82 (dd, J=8.42, 2.37 Hz, 1 H); 7.99 (d, J=2.28 Hz, 1H).

Example 16

Example 16 was synthesised in analogy to example 11.

Starting materials: Example 5f (150 mg; 0.64 mmol)+Example 1a (111 mg;0.77 mmol).

The crude was purified by preparative HPLC. Obtained 85 mg of thedesired compound.

-   Example 16 MS: 362 and 364 [M+H]⁺; HPLC-MS Method: Z003_S05; R_(t)    [min]: 1.12 isotopic pattern for 1 Cl observed Chiral SFC Method:    I_SA_20_IPA_NH₃_001 R_(t) [min]: 3.21; e.e. 100% ¹H NMR (400 MHz,    DMSO-d₆); δ ppm 1.90 (t, J=10.81 Hz, 1H); 2.11 (td, J=11.38, 3.33    Hz, 1H); 2.56-2.67 (m, 4H); 2.90 (br d, J=11.29 Hz, 1H); 3.41-3.60    (m, 3H); 3.83-3.89 (m, 2H); 7.04 (d, J=8.37 Hz, 1H); 7.15-7.20 (m,    2H); 7.43-7.48 (m, 2H); 7.67 (q, J=4.63 Hz, 1H); 7.80 (dd, J=8.39,    2.40 Hz, 1H); 8.04 (d, J=2.38 Hz, 1H).

Example 17

Example 17 was synthesised in analogy to example 11.

Starting materials: Example 5g (150 mg; content 90%; 0.58 mmol)+Example1a (100 mg; 0.69 mmol).

The crude was purified by preparative HPLC. Obtained 191 mg of thedesired compound.

-   Example 17 MS: 362 and 364 [M+H]⁺; isotopic HPLC-MS Method:    Z003_S05; R_(t) [min]: 1.08 pattern for 1 Cl observed Chiral SFC    Method: I_SA_20_IPA_NH₃_001 R_(t) [min]: 2.75; e.e. 100% ¹H NMR (400    MHz, DMSO-d₆); δ ppm: 1.89 (t, J=10.81 Hz, 1H); 2.05-2.16 (m, 1H);    2.52-2.67 (m, 4H); 2.89 (br d, J=11.43 Hz, 1H); 3.41-3.60 (m, 3H);    3.79-3.92 (m, 2H); 7.08 (d, J=8.39 Hz, 1H); 7.25-7.32 (m, 2H);    7.37-7.42 (m, 1H); 7.57 (dd, J=7.94, 1.58 Hz, 1H); 7.63-7.72 (m,    1H); 7.80 (dd, J=8.42, 2.38 Hz, 1H); 7.99 (d, J=2.36 Hz, 1H).

Example 19

Example 19 was synthesised in analogy to example 11.

Starting materials: Example 5h (150 mg; 0.69 mmol)+Example 1a (119 mg;0.83 mmol). The crude was purified by preparative HPLC. Obtained 147 mgof the desired compound.

-   Example 19 HPLC-MS Method: Z003_S05; R_(t) [min]: 1.04 MS: 346    [M+H]⁺R_(t)[min]: 2.11; e.e. Chiral SFC Method: I_SA_20_IPA_NH₃_001    100% ¹H NMR (400 MHz, DMSO-d₆); δ ppm: 1.89 (t, J=10.81 Hz, 1H);    2.10 (td, J=11.35, 3.25 Hz, 1H); 2.56-2.66 (m, J=4.71 Hz, 4H); 2.89    (br d, J=11.23 Hz, 1H); 3.41-3.60 (m, 3H); 3.83-3.89 (m, 2H); 7.10    (d, J=8.40 Hz, 1H); 7.21-7.37 (m, 4H); 7.62-7.72 (m, 1H); 7.80 (dd,    J=8.42, 2.38 Hz, 1H); 7.99 (d, J=2.34 Hz, 1H).

Example 29

Example 29 was synthesised in analogy to example 11.

Starting materials: Example 5i (250 mg; 60% content; 0.70 mmol) andExample 1a (127 mg; content 80%; 0.70 mmol). The crude was purified viapreparative HPLC.

Obtained 174 mg of the desired product.

-   Example 29 HPLC-MS ; Method: Z011_S03; R_(t) [min]: 0.94 MS: 342    (M+H)⁺ R_(t) [min]: 3.23; e.e. Chiral SFC Method::    I_SA_20_IPA_NH_(3—)001 99% ¹H NMR (400 MHz, DMSO-d₆); δ ppm: 1.89    (t, J=10.83 Hz, 1H); 2.06-2.14 (m, 1H); 2.30-2.33 (m, 3H); 2.54-2.67    (m, 4H); 2.86-2.92 (m, 1H); 3.40-3.59 (m, 3H); 3.83-3.89 (m, 2H);    6.93-7.02 (m, 3H); 7.20 (d, J=7.77 Hz, 2H); 7.64-7.70 (m, 1H); 7.75    (dd, J=8.46, 2.41 Hz, 1H); 8.02 (d, J=2.21 Hz, 1H).

Example 30

Example 30 was synthesised in analogy to Example 11.

Starting materials: Example 5j (150 mg; 0.69 mmol) and Example 1a (124.5mg; content 80%; 0.69 mmol). The crude was purified by preparative HPLC.

Obtained 157 mg of the desired compound.

-   Example 30 HPLC-MS ; Method: Z011_S03; R_(t) [min]: 0.89 MS:    346[M+H]⁺ R_(t) [min]: 2.22; e.e. Chiral SFC Method::    I_SA_20_IPA_NH₃_001 100% ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.98 (m,    1H); 2.18 (m, 1H); 2.55-2.59 (m, 3H); 2.64-2.71 (m, 1H); 2.95 (m,    1H); 3.55-3.65 (m, 3H); 3.84-3.91 (m, 2H); 7.11-7.16 (m, 2H);    7.22-7.28 (m, 2H); 7.37-7.47 (m, 2H); 7.68 (m, 1H) 8.28 (m, 1H).

Example 31

Example 1a (67.4 mg; 0.47 mmol) and example 5k (100 mg; 0.43 mmol) weredissolved in THF (3 ml); DIPEA (0.11 ml; 0.64 mmol) was added and thereaction mixture stirred 30 min before the addition of NaBH(OAc)3 (126mg; 0.60 mmol). The mixture was stirred over 3 hours at roomtemperature, diluted with MeOH, filtered through a syringe filter andpurified by preparative HPLC.

Obtained 53 mg of the desired compound.

-   Example 31 HPLC-MS ; Method: Z003_S05; R_(t) [min]: 1.074 MS: 364    (M+H)⁺ R_(t) [min]: 5.75; e.e. Chiral SFC Method::    G_IG_IPA_NH_(3—)001 94.8% ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.98 (m,    1H); 2.18 (m, 1H); 2.57 (m, 3H); 2.62-2.71 (m, 1H); 2.93 (m, 1H);    3.54-3.66 (m, 3H); 3.83-3.92 (m, 2H); 7.12-7.18 (m, 1H); 7.33-7.53    (m, 4H); 7.60-7.72 (m, 1H); 8.29 (m, 1H).

Example 32

Example 32 was synthesised in analogy to example 31.

Starting materials: Example 51(100 mg; 0.40 mmol) and Example 1a (63.0mg; 0.44 mmol).

The crude was purified by preparative HPLC. Obtained 21 mg of thedesired compound.

-   Example 32 MS: 380 and 382 [M+]⁺; HPLC-MS ; Method: Z003_S05; R_(t)    [min]: 1.139 isotopic pattern for 1 Cl observed Chiral SFC Method::    G_C4_MeOH_NH₃_001 R_(t) [min]: 4.26; e.e. 100% ¹H NMR (400 MHz,    DMSO-d₆) δ ppm: 1.99 (m, 1H); 2.18 (m, 1H); 2.57 (m, 3H); 2.62-2.75    (m, 1H); 2.94 (m, 1H); 3.55-3.66 (m, 3H); 3.83-3.92 (m, 2H);    7.26-7.35 (m, 2H); 7.41-7.48 (m, 2H); 7.62-7.72 (m, 2H); 8.33 (m,    1H).

Example 33

Example 33 was synthesised in analogy to example 31.

Starting materials: Example 5m (100 mg; 0.46 mmol) and Example 1a (73.0mg; 0.51 mmol). The crude was purified by preparative HPLC. Obtained 42mg of the desired compound.

-   Example 33 HPLC-MS ; Method: Z003_S05; R_(t) [min]: 1.056 MS: 346    [M+H]⁺ R_(t) [min]: 6.41; e.e. Chiral SFC Method:: G_IG_IPA_NH₃_001    100% ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.99 (m, 1H); 2.18 (m, 1H);    2.58 (m, 3H); 2.63-2.70 (m, 1H); 2.94 (m, 1H); 3.55-3.65 (m, 3H);    3.84-3.91 (m, 2H); 7.23-7.33 (m, 3H); 7.34-7.50 (m, 4H); 7.67 (m,    1H); 8.30 (m, 1H).

Example 34

Example 34 was synthesised in analogy to example 31.

Starting materials: Example 5n (100 mg; 0.43 mmol) and Example 1a (74.8mg; 0.52 mmol). The crude was purified by preparative HPLC.

Obtained 62 mg of the desired compound.

-   Example 34 HPLC-MS ; Method: Z003_S05; R_(t) [min]: 1.12 MS: 360    [M+H]⁺ R_(t) [min]: 5.96; Chiral SFC Method:: G_IG_MeOH_NH₃_001    e.e.:100% ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 1.98 (m, 1H); 2.12-2.23    (m, 1H); 2.33 (s, 3H); 2.57 (m, 3H); 2.62-2.69 (m, 1H); 2.93 (m,    1H); 3.54-3.64 (m, 3H); 3.83-3.91 (m, 2H); 7.03-7.09 (m, 1H); 7.16    (m, 1H); 7.24 (m, 1H); 7.32 (m, 1H); 7.42 (m, 1H); 7.66 (m, 1H);    8.26 (m, 1H).

Example 35

Example 35 was synthesised in analogy to example 31.

Starting materials: Example 5o (100 mg; 0.50 mmol) and Example 1a (79.6mg; 0.55 mmol). The mixture was stirred at room temperature overnight.The crude was purified by preparative HPLC. Obtained 95.0 mg of thedesired compound.

-   Example 35 HPLC-MS ; Method: Z011_S03; R_(t) [min]: 0.88 MS: 328    (M+H)⁺ R_(t) [min]: 2.5; Chiral SFC Method: : I_SA_20_IPA_NH_(3—)001    e.e.: 100% ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.00 (m, 1H) 2.19 (m, 1H)    2.58 (m, 3H) 2.68 (m, 1H) 2.96 (m, 1H) 3.56-3.65 (m, 3H) 3.84-3.92    (m, 2H) 7.07 (m, 2H) 7.18 (m, 1H) 7.39-7.48 (m, 4H) 7.62-7.72 (m,    1H) 8.29 (m, 1H)

Example 36

Example 36 was synthesised in analogy to example 31.

Starting materials: Example 5p (120 mg; 0.60 mmol) and Example 1a (95.5mg; 0.66 mmol). The mixture was stirred at room temperature during 18hours. The crude was purified by preparative HPLC. Obtained 140 mg ofthe desired compound.

-   Example 36 HPLC-MS ; Method: Z011_S03; R_(t) [min]: 0.88 MS: 328    [M+H]⁺ R_(t) [min]: 2.73; Chiral SFC Method:: I_SA_20_IPA_NH₃_001    e.e.:100% ¹H NMR (400 MHz, DMSO-d₆); δ ppm: 1.90 (m, 1H); 2.11 (m,    1H); 2.57 (m, 3H); 2.61-2.67 (m, 1H); 2.90 (m, 1H); 3.43-3.60 (m,    3H); 3.83-3.89 (m, 2H); 6.99 (d, J=8.37 Hz, 1H); 7.10-7.23 (m, 3H);    7.41 (t, J=7.53 Hz, 2H); 7.62-7.71 (m, 1H); 7.78 (dd, J=8.40, 2.41    Hz, 1H); 8.04 (d, J=2.36 Hz, 1H).

Example 37

Example 1a (76.9 mg; 0.53 mmol) and example 5q (120 mg; content 95%;0.49 mmol) were dissolved in THF (3 ml); DIPEA (0.12 ml; 0.68 mmol) wasadded and the reaction mixture stirred 30 min before the addition ofNaBH(OAc)₃ (126 mg; 0.60 mmol). The mixture was stirred over 18 hours atroom temperature, diluted with MeOH, filtered through a syringe filterand purified by preparative HPLC. The product was diluted with water (5ml) and the obtained precipitate is filtered off, washed with water anddried in the air. Obtained 106 mg of the desired compound.

-   Example 37 HPLC-MS ; Method: Z011_S03; R_(t) [min]: 0.93 MS: 364    (M+H)⁺ R_(t) [min]: 1.8; Chiral SFC Method: : I_SA_20_IPA_NH₃_001    e.e. 100% ¹H NMR (400 MHz, DMSO-d₆); δ ppm: 1.91 (m, 1H); 2.05-2.16    (m, 1H); 2.54-2.65 (m, 4H); 2.89 (m, 1H); 3.46-3.59 (m, 3H);    3.82-3.89 (m, 2H); 7.19-7.36 (m, 4H); 7.62-7.69 (m, 1H); 7.85 (m,    1H); 7.99 (m, 1H).

Example 38

Example 1a (75.8 mg; 0.53 mmol) and example 5r (130 mg; content 85%;0.48 mmol) were dissolved in THF (3 ml); DIPEA (0.12 ml; 0.67 mmol) wasadded and the reaction mixture stirred 30 min before the addition ofNaBH(OAc)₃ (152 mg; 0.72 mmol). The mixture was stirred over 18 hours atroom temperature, diluted with MeOH (3 ml), filtered through a syringefilter and purified by preparative HPLC.

Obtained 129 mg of the desired compound.

-   Example 38 HPLC-MS ; Method: Z003_S05; R_(t) [min]: 1.10 MS: 360    (M+H)⁺ R_(t) [min]: 1.9; Chiral SFC Method: : I_SA_20_IPA_NH₃_001    e.e. 100% ¹H NMR (400 MHz, DMSO-d₆); δ ppm: 1.89 (m, 1H); 2.05-2.14    (m, 4H); 2.57 (m, 3H); 2.60-2.65 (m, 1H); 2.89 (m, 1H); 3.41-3.59    (m, 3H); 3.82-3.90 (m, 2H); 7.09-7.19 (m, 4H); 7.64-7.70 (m, 1H);    7.80 (m, 1H); 7.96 (m, 1H).

Example 39

Example 39 was synthesised in analogy to example 38.

Starting materials: Example 5s (130 mg; content 85%; 0.47 mmol) andExample 1a (74.5 mg; 0.52 mmol). The mixture was stirred at roomtemperature during 18 hours.

The crude was purified by preparative HPLC. Obtained 75.0 mg of thedesired compound.

-   Example 39 HPLC-MS ; Method: Z003_S05; R_(t) [min]: 1.06 MS: 364    [M+H]⁺ R_(t) [min]: 1.98; Chiral SFC Method: : I_SA_20_IPA_NH₃_001    e.e.:100% ¹H NMR (400 MHz, DMSO-d₆); δ ppm: 1.98 (m, 1H); 2.17 (m,    1H); 2.57 (m, 3H); 2.61-2.69 (m, 1H); 2.93 (m, 1H); 3.54-3.65 (m,    3H); 3.83-3.91 (m, 2H); 7.31-7.45 (m, 5H); 7.67 (m, 1H); 8.32 (m,    1H).

Example 40

Example 40 was synthesised in analogy to example 38.

Starting materials: Example 5t (100 mg; 0.43 mmol) and Example 1a (67.43mg; 0.47 mmol).

The crude was purified by preparative HPLC. Obtained 130 mg of thedesired compound.

-   Example 40 HPLC-MS ; Method: Z003_S05; R_(t) [min]: 1.08 MS: 364    [M+H]⁺ R_(t) [min]: 1.78; Chiral SFC Method: : I_SA_20_IPA_NH₃_001    e.e.:100%

Example 41

Example 41 was synthesised in analogy to example 38.

Starting materials: Example 5u (100 mg; 0.4 mmol) and Example 1a (63 mg;0.44 mmol). Obtained 135 mg of the desired compound.

-   Example 41 MS: 380 and 382 [M+H]⁺; HPLC-MS ; Method: Z003_S05; R_(t)    [min]: 1.11 isotopic pattern for 1 Cl observed Chiral SFC Method::    I_SA_20_IPA_NH₃_001 R_(t) [min]: 2.22; e.e.:100%

What is claimed is:
 1. A compound of formula A

or a pharmaceutically acceptalble salt thereof, wherein X₁ is N and X₂is CH, or X₁ is CH and X₂ is N, R¹ is selected from the group consistingof methyl, ethyl, propyl, iso-propyl, cyclopropyl, H₃C—CH₂—CH₂—CH₂—, andcyclobutyl; and R² is phenyl which is optionally substituted with 1, 2or 3 substituents selected from the group consisting of fluoro, chloro,methyl, ethyl, and cyclopropyl.
 2. The compound according to claim 1,having the structure of formula A1 or of formula A2

in which R¹ and R² have the same meaning as defined in claim 1, or apharmaceutically acceptalble salt thereof.
 3. The compound according toclaim 1, or a pharmaceutically acceptalble salt thereof wherein R¹ ismethyl; and R² is selected from the group consisting of:


4. The (S)-enantiomer according to claim 1, or a pharmaceuticallyacceptable salt thereof, selected from the group consisting of: Ex. 11

12

13

14

15

16

17

19

29

30

31

32

33

34

35

36

37

38

39

40

41


5. A pharmaceutically acceptable salt of a compound according toclaim
 1. 6. A method for treating and/or preventing bipolar disorder Idepressed, hypomanic, manic and mixed form, bipolar disorder II,depressive disorders, major depressive disorder with or withoutconcomitant anxious distress, mixed features, melancholic features,atypical features, mood-congruent psychotic features, mood-incongruentpsychotic features, or catatonia, the method comprising administering apharmaceutically effective amount of a compound of formula A accordingto claim 1, or a pharmaceutically acceptable salt thereof, to a patientin need thereof.
 7. A method for treating and/or preventing singledepressive episode or recurrent major depressive disorder, minordepressive disorder, depressive disorder with postpartum onset, ordepressive disorders with psychotic symptoms, the method comprisingadministering a pharmaceutically effective amount of a compound offormula A according to claim 1, or a pharmaceutically acceptable saltthereof, to a patient in need thereof.
 8. The method according to claim6, wherein the compound of of formula A, or a pharmaceuticallyacceptable salt thereof, is administered with another antidepressantdrug.
 9. The method according to claim 6, wherein the patient is furtherbeing treated with behavioural therapy.
 9. The method according to claim7, wherein the compound of formula A, or a pharmaceutically acceptablesalt thereof, is administered with another antidepressant drug.
 10. Themethod according to claim 7, wherein the patient is further beingtreated with behavioural therapy.
 11. A pharmaceutical compositioncomprising a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, in admixture with a pharmaceutically acceptableadjuvant, diluent and/or carrier.